Abstract
It is likely that the heritability of T2DM goes beyond simple genetic markers and involves epigenetic mechanisms. Neels Thrifty Gene Hypothesis was expanded by Chakravarthy to include metabolic cycling and the dissonance between our stone-age genes with a space-age lifestyle. Further modifications of this hypothesis continued after recent developments in evolutionary and epigenetic research. At the molecular forefront, energy-sensing signaling pathways in T2DM, such as PGC1α, AMPK, O-GlcNAc and most recently SIRT1 have been shown to play key roles in oxidative stress, mitochondrial dysfunction, inflammation and glucolipotoxicity, which are the hallmarks of insulin resistance and T2DM, Furthermore, SIRT1, PGC1α and O-GlcNAc also regulate gene expression and may play a role in the epigenetic machinery, thus providing an explanation to how metabolism switches to either a thrift or spend mode depending on food availability. Separate evidence on adaptations to exercise further links T2DM with decreased physical activity. In this review, the major findings from the epigenetic, epidemiological, molecular and clinical forefronts are integrated and unified as a coherent hypothesis for the etiology and pathogenesis of T2DM. It is an opportune time to start connecting the dots to provide the much needed basis for a better understanding of T2DM and a more targeted approach to drug development and treatment strategies.
Keywords: Diabetes, Exercise, Epigenetics, Energy metabolism, Caloric restriction
Current Diabetes Reviews
Title: Connecting the Dots: Molecular and Epigenetic Mechanisms in Type 2 Diabetes
Volume: 6 Issue: 4
Author(s): Kian-Peng Goh and Chee-Fang Sum
Affiliation:
Keywords: Diabetes, Exercise, Epigenetics, Energy metabolism, Caloric restriction
Abstract: It is likely that the heritability of T2DM goes beyond simple genetic markers and involves epigenetic mechanisms. Neels Thrifty Gene Hypothesis was expanded by Chakravarthy to include metabolic cycling and the dissonance between our stone-age genes with a space-age lifestyle. Further modifications of this hypothesis continued after recent developments in evolutionary and epigenetic research. At the molecular forefront, energy-sensing signaling pathways in T2DM, such as PGC1α, AMPK, O-GlcNAc and most recently SIRT1 have been shown to play key roles in oxidative stress, mitochondrial dysfunction, inflammation and glucolipotoxicity, which are the hallmarks of insulin resistance and T2DM, Furthermore, SIRT1, PGC1α and O-GlcNAc also regulate gene expression and may play a role in the epigenetic machinery, thus providing an explanation to how metabolism switches to either a thrift or spend mode depending on food availability. Separate evidence on adaptations to exercise further links T2DM with decreased physical activity. In this review, the major findings from the epigenetic, epidemiological, molecular and clinical forefronts are integrated and unified as a coherent hypothesis for the etiology and pathogenesis of T2DM. It is an opportune time to start connecting the dots to provide the much needed basis for a better understanding of T2DM and a more targeted approach to drug development and treatment strategies.
Export Options
About this article
Cite this article as:
Goh Kian-Peng and Sum Chee-Fang, Connecting the Dots: Molecular and Epigenetic Mechanisms in Type 2 Diabetes, Current Diabetes Reviews 2010; 6 (4) . https://dx.doi.org/10.2174/157339910791658899
DOI https://dx.doi.org/10.2174/157339910791658899 |
Print ISSN 1573-3998 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6417 |
![](/images/wayfinder.jpg)
- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Natriuretic Peptide Family: New Aspects
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Update on Pharmacologic Approaches to Prevent Thromboembolism in Atrial Fibrillation: Are Thrombin and Factor Xa Inhibitors the Ultimate Answer?
Current Vascular Pharmacology Arrhythmias and Left Ventricular Hypertrabeculation/Noncompaction
Current Pharmaceutical Design Adiponectin and its Receptors as Potential Therapeutical Targets
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Glucose Sensors Based on Core@Shell Magnetic Nanomaterials and Their Application in Diabetes Management: A Review
Current Pharmaceutical Design Hypothalamic mTOR: The Rookie Energy Sensor
Current Molecular Medicine Side Effects of Clozapine and Some Other Psychoactive Drugs
Current Drug Safety Oxidative Stress and Vascular Disease
Current Hypertension Reviews Patent Selections
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery (Discontinued) Hemostatic Factors and the Metabolic Syndrome
Current Vascular Pharmacology Lipid Disorders in Pregnancy
Current Pharmaceutical Design Chemical Characterization and Antioxidant Potential of <i>Athroisma proteiformis</i> Essential Oil
The Natural Products Journal The Stress-Vulnerability Model of Schizophrenia: A Conceptual Analysis and Selective Review
Current Psychiatry Reviews Risk Models and Scores of Cardiovascular Disease in Patients with Diabetes Mellitus
Current Pharmaceutical Design Resveratrol and Analogues: A Review of Antioxidant Activity and Applications to Human Health
Recent Patents on Food, Nutrition & Agriculture The New Adipose Tissue and Adipocytokines
Current Diabetes Reviews Editorial (Hot Topic: Hypertension: A Serious Complication in Pregnancy)
Current Hypertension Reviews A New Short Validated U-HPLC Method for the Determination of Recombinant Human Insulin in Microspheres
Current Pharmaceutical Analysis Induced Pluripotent Stem Cells (iPSCs) Derived from Different Cell Sources and their Potential for Regenerative and Personalized Medicine
Current Molecular Medicine The Chemokine System as a Therapeutic Target in Autoimmune Thyroid Diseases: A Focus on the Interferon-γ Inducible Chemokines and their Receptor
Current Pharmaceutical Design